Pharmacological compositions for the treatment and prevention of coronavirus disease

ABSTRACT

Compositions and methods for treatment and prevention of coronavirus disease (COVID-19) and related diseases are provided. In one or more embodiments, the composition comprises two or more active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients.

RELATED APPLICATION

This application claims priority to U. S. Provisional Application Ser. No. 63/107,139 filed Oct. 29, 2020 and titled “PHARMACOLOGICAL COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF CORONAVIRUS DISEASE,” the entirety of which application is incorporated herein by reference.

TECHNICAL FIELD

This application relates to pharmacological compositions for the treatment and prevention of disease caused by a coronavirus, particularly the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related viruses.

BACKGROUND

Starting in December 2019, a novel coronavirus, designated SARS-CoV-2 has caused an international and rapidly growing pandemic of respiratory illness termed COVID-19 (also referred to as coronavirus disease). The full spectrum of COVID-19 ranges from a mild, self-limiting respiratory disease course to severe progressive pneumonia, multiorgan failure, and death. Thus far, there are no specific therapeutic agents for coronavirus infections. In less than six months of the pandemic, there have been over four million people with a confirmed diagnosis of COVID-19 and over 300,000 deaths worldwide, with the United States being the worst affected country with over one million confirmed cases.

Healthcare systems around the world are becoming increasingly strained and there is currently a desperate need of a safe and effective treatment for COVID-19. As of May 2020, no effective treatment for COVID-19 exists and there are no antiviral drugs approved by the Food and Drug Administration (FDA) to prevent and treat patients with COVID-19. There are also currently no repurposed drugs approved by the FDA to treat patients with COVID-19. Current COVID-19 treatment guidelines from the Center for Disease Control (CDC) only provide for hospitalization for supportive management. The Infectious Diseases Society of America has also released seven guidelines for the management of COVID-19 patients. As of May 2020, six of the seven guidelines recommend using experimental drugs such as hydroxychloroquine, azithromycin, and others only when administered in the context of a clinical trial. The seventh recommendation discourages the use of corticosteroids.

SUMMARY

The following presents a summary to provide a basic understanding of one or more embodiments of the present disclosure. This summary is not intended to identify key or critical elements or to delineate any scope of the particular embodiments or any scope of the claims. Its sole purpose is to present concepts in a simplified form as a prelude to the more detailed description that is presented later. The disclosed subject matter is directed to pharmacological compositions for the treatment and prevention of COVID-19 and related diseases.

According to an embodiment, a composition for the treatment and prevention of disease caused by a coronavirus is provided, the composition having active ingredients comprising: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of these active ingredients. In some implementations, the active ingredients may further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof. In various embodiments, the coronavirus comprises SARS-CoV-2 and derivatives thereof, and the composition is effective in treating and/or preventing coronavirus disease (COVID-19) in humans and other mammals. According to another embodiment, a method for treating or inhibiting a disease in a patient caused by a virus is provided. The method comprises administering an effective amount of an antiviral composition to the patient, the antiviral composition having active ingredients comprising: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients. In various embodiments, the coronavirus comprises SARS-CoV-2 and derivatives thereof, and the composition is effective in treating and/or preventing coronavirus disease (COVID-19) in humans and other mammals.

In another embodiment, an antiviral composition is provided that serves a broad-spectrum antiviral therapeutic agent. The antiviral composition comprises two or more active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc citrate dihydrate, copper gluconate, epigallocatechin gallate, quercetin dihydrate, hesperidin, caffeic acid, and bovine lactoferrin. In some implementations, the active ingredients may further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C provide a table identifying ingredients of one or more pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

FIG. 2 illustrates the SARS-CoV-2 lifecycle within a human cell and the mechanisms of action of active ingredients of the disclosed pharmacological compositions in accordance with one or more embodiments of the disclosed subject matter.

FIGS. 3A-3B provide another table describing antiviral mechanisms of different ingredients of one or more pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

FIG. 4 provides another table describing antiviral mechanisms of some additional active ingredients of one or more pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

FIG. 5 provides a high-level flow diagram of a method for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

FIG. 6 provides a high-level flow diagram of another method for treating coronavirus disease (COVID-19) in a patient in accordance with one or more embodiments of the disclosed subject matter.

FIG. 7 provides a high-level flow diagram of a method for inhibiting a viral disease in a patient in accordance with one or more embodiments of the disclosed subject matter.

FIG. 8 provides a high-level flow diagram of another method for treating a viral disease in a patient in accordance with one or more embodiments of the disclosed subject matter.

DETAILED DESCRIPTION

The following detailed description is merely illustrative and is not intended to limit embodiments and/or application or uses of embodiments. Furthermore, there is no intention to be bound by any expressed or implied information presented in the preceding Technical Field or Summary sections, or in the Detailed Description section.

The disclosed subject matter is directed to pharmaceutical compositions for the treatment and prevention of coronavirus disease (COVID-19) and related diseases. The disclosed pharmaceutical compositions can also provide broad spectrum antiviral activity against other viruses, including but not limited to, influenza virus, herpesvirus, cytomegalovirus, human immunodeficiency virus (HIV), and other viruses.

The pharmaceutical compositions employ unique combinations of vitamins, minerals, and botanicals and can be administered to patients using dosages easily achieved with ordinary food intake. In various embodiments, the active ingredients comprise ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients. In some embodiments, the active ingredients can comprise different combinations of two or more the above noted active ingredients and derivatives thereof. The active ingredients the active ingredients may further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof. The combinations of the specific ingredients employed in the antiviral compositions can result in multiple synergistic antiviral effects which have the potential to both prevent and treat COVID-19 with low or no toxicity in humans and other mammals.

The disclosed pharmaceutical compositions can also be used to treat and/or prevent mutations of SARS-CoV-2, other diseases caused by different types of coronaviruses, including severe acute respiratory syndrome (SARS) coronavirus, and related diseases. In some embodiments, the disclosed pharmaceutical compositions can also be used for the treatment and/or prophylaxis of other diseases and/or conditions that may be related to COVID-19, exacerbated by COVID-19, and/or that may make hosts more susceptible to more severe clinical complications of the disease, including but not limited to: chronic lung disease, asthma, heart disease, heart conditions, immune disorders, diabetes, kidney disease, liver disease, hemoglobin disorders, cancer and combinations thereof. In this regard, the disclosed compositions can be used as a broad-spectrum antiviral agent for the treatment and prevention of a variety of viruses.

Also provided are methods of treating and/or preventing disease caused by a coronavirus and other viruses in humans and other mammals. The methods typically involve administering one or more of dosages of the disclosed pharmaceutical compositions to the patient daily in an amount sufficient to inhibit growth and/or proliferation of the virus. In various embodiments, the pharmaceutical compounds can be administered orally (e.g., in the form of a capsule, pill, or the like), intravenously or in another suitable form. In certain embodiments the amount is an amount sufficient to exterminate or kill the virus. In some embodiments, the disclosed compositions can be administered to patients who have not contracted COVID-19 (or a related disease) to prevent contracting the disease. In other embodiments, the disclosed compositions can be administered to patients who have tested positive for COVID-19 (or a related disease) to treat the disease to minimize or eliminate the infection (e.g., to kill the virus) and/or to otherwise facilitate recovery from the disease.

The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable liquid or solid carriers as well as pharmaceutically acceptable additives. The disclosed pharmaceutical compositions can also be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, etc. that are commonly used in the preparation of medications and dietary supplements.

The solid form preparations may be tablets, pills, powders, granules, capsules, pellets, granules or powders, and such solid preparations may be prepared by adding a carrier, excipients and/or diluents to the compound. The carrier, excipient and/or diluent may include lactose, sucrose, dextrose, mannitol, malitol, sorbitol, xylitol, and erythritol. (erithritol), starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, polyvinyl pyrrolidone polyvinyl pyrrolidone, magnesium stearate, and mineral oil.

The formulations in liquid form may be solutions, suspensions or emulsions, and may include various excipients, for example wetting agents, sweeteners, fragrances, preservatives, etc., in addition to the commonly used simple diluents, water and liquid paraffin. Aqueous suspensions suitable for oral use may be prepared by dispersing the finely divided active ingredients in a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and known suspending agents.

Examples of fillers that can be used in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powder cellulose, magnesium stearate, microcrystalline cellulose, dexrate, kaolin, mannitol, silicic acid, silica, sorbitol, Starch, pre-gelatin ring starch, and mixtures thereof, including but not limited to. The binder or filler of the disclosed pharmaceutical compositions can be generally present in suitable amounts (e.g., about 50 to about 99 weight percent of the pharmaceutical composition or dosage form).

Disintegrants that can be used in the pharmaceutical compositions and dosage forms disclosed herein are intended to disintegrate when the tablet is exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little do not disintegrate at the desired rate under the desired conditions. A sufficient amount of disintegrant, therefore not too much or too little, should not be used to form the solid oral dosage form of the invention so as not to be bad for controlling the release of the active ingredient. The amount of disintegrants used varies depending on the type of formulation and can be readily determined by one of ordinary skill in the art. Typical pharmaceutical compositions contain about 0.5 to about 15 weight percent of disintegrant, preferably about 1 to about 5 weight percent of disintegrant. Some example disintegrants that can be used in the disclosed antiviral compositions can include but are not limited to: agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, poracryline potassium, sodium starch glycolenmit, potato or tapioca starch, other starch, pre-gelatinized starch, other starch, clay, other algins, other celluloses, gums, and mixtures thereof.

Glidants that can be used in the pharmaceutical compositions and dosage forms of the present invention are calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium Lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants are, for example, siloid silica (AEROSIL200, manufactured by WR Grace Co., Baltimore, Md.), coagulated aerosol of synthetic silica, manufactured by Degussa Co., Plano, Tex., CAB-O-SIL (pyrogenic silicon dioxide product, Cabot Co., Boston, Mass.), and mixtures thereof. If used, glidants are generally used in amounts up to about 1.0 percent weight t of the pharmaceutical composition or dosage form in which they are contained.

The pharmaceutical compositions of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes, and all modes of administration can be expected. For example, the compositions can be administered orally or parenterally, including by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, intrauterine, epidural or intracerebroventricular injection, or the like. Examples of the parenteral administration include injections, drops, sap, ointments, sprays, suspensions, emulsions, suppositories, and the like. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate may be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, and the like may be used.

As used herein, the terms “treatment” and/or “inhibition” means obtaining the desired pharmacological and/or physiological effect. Such an effect may be a prophylactic effect in terms of completely or partially suppressing a disease or symptoms thereof and/or may be a therapeutic effect in terms of partially or fully curing the adverse effects caused by the disease and/or disease. The terms “treatment” and/or “inhibition” as used herein encompasses any treatment for diseases of mammals, particularly humans. The terms “treatment” and/or “inhibition” as used herein can refer to treating and/or inhibiting disease applied to subjects susceptible to the disease but not yet diagnosed as diseased; preventing the development of the disease; inhibiting the disease (e.g., arresting the onset of the disease); and/or alleviating the disease (e.g., causing regression of the disease).

The pharmaceutical compositions disclosed herein are intended to be administered in a therapeutically effective amount upon administration for clinical purposes. The term “therapeutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective amount for a particular patient based on relevant patient variables (e.g., age, sex, weight, health status, medical history, comorbidities, underlying conditions, etc.), time of administration, route of administration, rate of excretion, active ingredient mixture and ratios, and severity of disease. However, for the desired effect, the one or more of the disclosed pharmaceutical compounds may be administered in an amount of 0.0001 to 1000 milligrams per kilogram (mg/kg) divided once or several times a day, and preferably in the form of a 750 mg capsule administered twice daily.

The amount of the active ingredients of the disclosed pharmaceutical compositions can be combined with a substance such as a carrier to produce a dosage form can vary depending upon the host to be treated and the particular mode of administration. The composition may contain from 0.001 to 95% of the active ingredients, and a typical pharmaceutical formulation may contain from about 5% to about 95% of the active ingredient (w/w). In another embodiment, the pharmaceutical formulations described herein may contain about 20% to about 80% active ingredients.

Those skilled in the art will readily understand that dosage levels may vary as a function of specific coronavirus inhibitory compounds, the severity of symptoms and the subject's susceptibility to side effects. Preferred dosages of pharmaceutical compositions comprising the active ingredients disclosed herein can be readily determined by one skilled in the art by a variety of means.

In many embodiments, multiple doses of the pharmaceutical compositions disclosed herein are administered to achieve the desired therapeutic effect. For example, about 1 week to about 2 weeks, about 2 weeks to about 4 weeks, about 1 month to about 2 months, about 2 months to about 4 months, about 4 months to about 6 months, about 6 months after virus exposure. In another embodiment, the disclosed pharmaceutical compositions can be administered once a month, twice a month, three times a month, over a period of about 8 months, about 8 months to about 1 year, about 1 year to about 2 years, about 2 years to about 4 years, or more. In another example embodiment, the pharmaceutical compounds disclosed herein can be administered every other week, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, every other day, every day, twice a day or three times a day.

In many embodiments, the pharmaceutical compounds containing the active ingredients disclosed herein inhibit coronavirus replication. For example, the compounds of the present invention may inhibit coronavirus replication at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, as compared to coronavirus replication in the absence of the disclosed pharmaceutical compounds. In another embodiment, the disclosed pharmaceutical compounds can inhibit coronavirus replication by at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% or more. Whether the compounds of the present invention inhibit coronavirus replication can be determined using methods known in the art, such as in vitro virus replication assays. As used herein, the term “coronavirus” includes any member of the family of coroniviridae, including but not limited to any member of the genus Coronavirus and/or any member of the genus Torovirus. Coronaviridae is a family of viruses characterized by irregular shaped particles of 60-220 nanometers (nm) in diameter with a distinctive club-shaped perfluorometer with an envelope on the outside, which gives the virus a crown-like appearance. Coronoviridae includes the genus Coronavirus and Toro virus. Coronaviruses include infectious bronchitis virus (IBV), bovine coronavirus (BCoV), bat coronavirus BatCoV RaTG13, canine coronavirus (CCoV), feline coronavirus (FeCoV), porcine erythrocyte aggregated encephalomyelitis virus (PEDV), mouse hepatitis virus (MHV), and turkey coronavirus (TCoV), infectious gastrointestinal virus (TGEV), rat coronavirus (RCV), human coronavirus 229E (HCoV-229E), human coronavirus NL63 (NL), human coronavirus OC43 (HCoV-OC43), SARS coronavirus (SARS-CoV), SARS-CoV-2, and the like, but is not limited thereto. Toro viruses include, but are not limited to, Berne virus and Breda virus.

The present invention provides a pharmaceutical composition for the treatment and prevention of diseases caused by any one of the coronaviruses, and preferably provides a pharmaceutical composition for the treatment and prevention COVID-19 caused by SARS-CoV-2 coronavirus. The disclosed pharmaceutical compositions can also provide broad spectrum antiviral activity against other viruses, including but not limited to, influenza virus, herpesvirus, cytomegalovirus, HIV, and other viruses.

Further, the term “coronavirus” includes naturally occurring (e.g., wild type) coronaviruses, naturally occurring coronavirus variants, variants generated by selection, variants generated by chemical modifications, genetically modified variants (e.g., coronaviruses modified by recombinant DNA methods in the laboratory) and include laboratory generated coronavirus variants.

The term “specificity” when used with respect to antiviral activity of the disclosed pharmaceutical compounds indicates that the compound preferentially inhibits growth and/or proliferation and/or exterminates a particular virus as compared to mammalian red blood cells (RBCs). In certain embodiments the preferential inhibition or exterminate is at least 10% greater (e.g., the LD₅₀ being 10% lower), preferably at least 20%, 30%, 40%, or 50%, more preferably at least 2-fold, at least 5-fold, or at least 10-fold greater for the target virus.

The term “high” as used with respect to antiviral activity and/or potency is used herein to indicate that the level of antiviral activity of an antiviral compound disclosed herein is greater than a defined minimum threshold of antimviral activity or potency for a particular coronavirus. In various embodiments, the minimum threshold can be based on its minimum inhibitory concentration (MIC), its LD₅₀ concentration/or its HC₅₀, concentration, wherein the lower the concentration, the higher the antiviral activity and/or potency. For example, in some embodiments, an antiviral composition disclosed herein can be considered to have high antiviral activity and/or potency if its MIC is less than 250 micrograms per milliliter (μg/mL), more preferably less than 150 μg/mL, more preferably less than 100 μg/mL, more preferably less than 50 μg/mL, and even more preferably less than 30 μg/mL.

The term “low-toxicity” is used herein to indicate any level of toxicity of a pharmacological composition that is less than defined acceptable threshold of toxicity. In various embodiments, the defined threshold can be based on the MIC of the pharmacological composition relative to its LD₅₀ and/or HC₅₀ concentration. In some implementations, a pharmacological composition disclosed herein can be considered to have low-toxicity if its MIC is less than its LD₅₀ and/or HC₅₀ concentration. In other implementations, a pharmacological composition can be considered to have low-toxicity if its MIC is 60% or less than its LD₅₀ and/or HC₅₀ concentration. In other implementations, a pharmacological composition can be considered to have low-toxicity if its MIC is 50% or less than its LD₅₀ and/or HC₅₀ concentration. In other implementations, a pharmacological composition can be considered to have low-toxicity if its MIC is 30% or less than its LD₅₀ and/or HC₅₀ concentration. In other implementations, a pharmacological composition can be considered to have low-toxicity if its MIC is 25% or less than its LD₅₀ and/or HC₅₀ concentration.

One or more embodiments are now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a more thorough understanding of the one or more embodiments. It is evident, however, in various cases, that the one or more embodiments can be practiced without these specific details. It is noted that the drawings of the present application are provided for illustrative purposes only and, as such, the drawings are not drawn to scale.

FIGS. 1A and 1B provide a table (Table 100) identifying ingredients of one or more pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter. The pharmacological compositions comprising the active ingredients listed in Table 100 can also function as broad-spectrum antiviral agents for the treatment and prevention of other viral diseases. Table 100 lists nine different active ingredients that can be included in one or more pharmaceutical compositions for the treatment and/or prevention of disease caused by a coronavirus (e.g., SARS-CoV-2) and other viruses. These ingredients include ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients. Table 100 further provides the chemical structures of the active ingredients.

In some embodiments, an effective pharmacological composition for the treatment and/or prevention of diseases (e.g., COVID-19) caused by and/or exacerbated by a coronavirus (e.g., SARS-CoV-2 and related viruses) can comprise effective amounts of all nine ingredients listed in Table 100 (or derivatives thereof). The active ingredients can be combined for example in a pill or capsule and administered orally. According to these embodiments, per single unit (e.g., single capsule, pill or another form), the pharmacological composition can comprise the following amounts of the respective active ingredients: about 30.0 milligrams (mg) to about 120 mg of ascorbic acid, more preferably about 50.0 mg to about 100 mg of ascorbic acid, even more preferably about 60.0 mg to about 80.0 mg of ascorbic acid; about 5.0 micrograms (μg) to about 50.0 μg of cholecalciferol, more preferably about 10.0 μg to about 40 μg of cholecalciferol, and even more preferably about 15.0 μg to about 25.0 μg of cholecalciferol; about 0.5 mg to about 20 mg of zinc, more preferably, about 1.0 mg to about 15.0 mg of zinc, and even more preferably about 3.0 mg to about 7.0 mg of zinc; about 0.05 mg to about 5.0 mg of copper, more preferably about 0.1 mg to about 2.0 mg of copper, and even more preferably about 0.15 mg to about 1.0 mg of copper; about 10.0 mg to about 100 mg of epigallocatechin gallate (EGCG), more preferably about 30.0 mg to about 80.0 mg of EGCG, and even more preferably about 40.0 mg to about 60.0 mg of EGCG; about 50.0 mg to about 150 mg of quercetin, more preferably about 70.0 mg to about 130 mg of quercetin, and even more preferably about 80.0 mg to about 100 mg of quercetin; about 30.0 mg to about 120 mg of hesperidin, more preferably about 50.0 mg to about 100 mg of hesperidin, even more preferably about 60.0 mg to about 80.0 mg of hesperidin; about 10.0 mg to about 100 mg of caffeic acid, more preferably about 30.0 mg to about 80.0 mg of caffeic acid, and even more preferably about 40.0 mg to about 60.0 mg of caffeic acid; about 10.0 mg to about 100 mg of bovine lactoferrin, more preferably about 30.0 mg to about 80.0 mg of bovine lactoferrin, and even more preferably about 40.0 mg to about 60.0 mg of bovine lactoferrin.

The above noted amounts of the active ingredients correspond the amounts of the respective active ingredients per unit of the pharmacological composition. In this regard, it should be appreciated that the composition can be discretized into units (e.g., encapsulated units, or another form), and wherein each unit (e.g., each capsule, pill, etc.) comprises the active ingredients in accordance with one or more of the above noted amounts. In accordance with these amounts, the effective dose can range between one and ten units per day, which can vary based on the patient (with respect to patient condition, age, weight, comorbidities, etc.) and the amounts of the active ingredients included in each unit. For example, in some implementations, the effective dose may include two to four units daily. In other implementation, the effective dose may include three to six units daily (e.g., three units taken twice daily).

For instance, in accordance with one example implementation, each unit (e.g., each capsule) comprises about 30.0 mg to about 120 mg of ascorbic acid, about 5.0 μg to about 50.0 μg of cholecalciferol, about 0.5 mg to about 20 mg of zinc, about 0.05 mg to about 5.0 mg of copper, about 10.0 mg to about 100 mg of epigallocatechin gallate, about 50.0 mg to about 150 mg of quercetin, about 30.0 mg to about 120 mg of hesperidin, about 10.0 mg to about 100 mg of caffeic acid, and about 10.0 mg to about 100 mg of bovine lactoferrin, and the effective dose comprises between one and ten units per day, more preferably, two to four units per day, and even more preferably three to six units per day.

In other implementation, each unit (e.g., each capsule) comprises about 50.0 mg to about 100 mg of ascorbic acid, about 10.0 m to about 40.0 m of cholecalciferol, about 1.0 mg to about 15 mg of zinc, about 0.1 mg to about 2.0 mg of copper, about 30.0 mg to about 80 mg of epigallocatechin gallate, about 70.0 mg to about 130 mg of quercetin, about 50.0 mg to about 100 mg of hesperidin, about 30.0 mg to about 80 mg of caffeic acid, and about 30 mg to about 80 mg of bovine lactoferrin, and the effective dose comprises between one and ten units per day, more preferably, two to four units per day, and even more preferably three to six units per day. In other implementation, each unit (e.g., each capsule) comprises about 60 mg to about 80 mg of ascorbic acid, about 15.0 m to about 25.0 μg of cholecalciferol, about 3.0 mg to about 7 mg of zinc, about 0.15 mg to about 1.0 mg of copper, about 40.0 mg to about 60 mg of epigallocatechin gallate, about 80.0 mg to about 100 mg of quercetin, about 60.0 mg to about 80 mg of hesperidin, about 40.0 mg to about 60 mg of caffeic acid, and about 40 mg to about 60 mg of bovine lactoferrin, and the effective dose comprises between one and ten units per day, more preferably, two to four units per day, and even more preferably three to six units per day.

In another embodiment, an effective pharmacological composition for the treatment and/or prevention of diseases (e.g., COVID-19) caused by and/or exacerbated by a coronavirus (e.g., SARS-CoV-2 and related viruses) can comprise a subset of the nine active ingredients listed in Table 100. For example, in some embodiments, the pharmacological composition can comprise eight, seven, six, five, four, three or only two of the active ingredients listed in Table 100. For example, in some embodiments, copper and/or zinc may be removed from the composition yet still provide antiviral and other therapeutic effect for patients with sensitivity to zinc and/or copper. According to these embodiments, the amounts of the respective ingredients as included in the pharmacological composition can adhere to the ranges and amounts described above.

The combination of the specific ingredients employed in the subject pharmaceutical compositions can result in multiple synergistic antiviral effects which have the potential to both prevent and treat COVID-19 with low or no toxicity in humans and other mammals. In this regard, the pharmaceutical compositions described herein can treat and inhibit infection of SARS-CoV-2 and other coronaviruses in human cells using different mechanisms of action attributed to one or more synergistic combinations of the active ingredients listed in Table 100.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus, contagious in humans and spread via close contact and via respiratory droplets from coughs or sneezes. The genome of SARS-CoV-2 consists of approximately 29700 nucleotides, about 80% and 96% identical to the SARS-CoV and the bat coronavirus BatCoV RaTG13 genomes, respectively. SARS-CoV-2 has four structural proteins, known as the spike protein (also referred to as the S protein), the envelope protein (also referred to as the E protein), the membrane protein (also referred to as the M protein), and the nucleocapsid protein (also referred to as the N protein). The N protein holds the RNA genome, and the S, E, and M proteins together create the viral envelope.

The disclosed pharmaceutical compositions target multiple areas of the coronavirus via both direct and indirect antiviral actions. In various embodiments, the disclosed compositions can treat and inhibit infection of the virus in human cells based on direct or indirect disruption of one or more biological targets of the coronavirus caused by one or more of the active ingredients, wherein the one or more biological targets are selected from a group consisting of: spike protein, helicase (nsp13), RNA-dependent RNA polymerase (RdRp), propapain-like protease (PLpro), and chymotrypsin-like protease (3CLpro).

The spike protein allows the SARS-CoV-2 virus to attach to and fuse with the membrane of a host cell by binding to the angiotensin converting enzyme 2 (ACE2) receptor. As described in greater detail below, one or more of the active ingredients included in Table 100 can directly or indirectly interfere with the spike protein and ACE2 receptor interaction to prevent or minimize binding of the SARS-CoV-2 virus (and related viruses) with the ACE2 receptor of the host cell.

Helicase, also known as Nsp13, is a multi-functional protein with an N-terminal metal binding domain and helicase domain and is a necessary component for the replication of coronavirus. Helicase inhibition would also therefore help block viral replication. RdRp, also known as nsp12, is a non-structural protein that is required for SARS-CoV-2 replication. The overall architecture of the COVID-19 virus nsp12-nsp7-nsp8 complex is similar to that of SARS-CoV with a root-mean-square deviation value of 0.82.

PLpro is responsible for the cleavages of N-terminus of the replicase poly-protein to release Nsp1, Nsp2 and Nsp3, which is essential for correcting SARS-CoV-2 replication.

3CLpro is the main protease in SARS-CoV-2 and is essential for processing the polyproteins that are translated from viral RNA. Inhibition of 3CLpro production would help block viral replication. By sequence alignment (as shown below), the SARS-CoV-2 and SARS-CoV 3CLpro genes share a remarkable 96% sequence identity (their corresponding proteins only differ by 12 amino acids), and the crystal structure of SARS-CoV-2 3CLpro is highly similar to its SARS sister (PDB ID: 2DUC) with very similar binding sites.

The disclosed anti-coronavirus compositions contain multiple ingredients found in nature. The rationale for the use of multiple ingredients and dosages in the disclosed compositions as opposed to using a single agent alone are numerous.

Firstly, the disclosed compositions are designed to be safe for use in humans and other mammals. The ingredients listed in Table 100 are a combination of micronutrients and flavonoids that are well tolerated, well-studied, and are either found in common foods or have a long safety history in human consumption. All of the dosages of the specific ingredients in the disclosed compositions are all within the upper tolerable safety limits set by the United States Institute of Medicine. The tolerable upper limit (UL) is defined by the United States Institute of Medicine as the maximum daily intake level at which no risk of adverse health effects is expected for almost all individuals in the general population, including sensitive individuals, when the nutrient is consumed over long periods of time. In other words, the UL is the highest usual intake level of a nutrient that poses no risk of adverse effects.

Secondly, the combination of the specific ingredients in the disclosed pharmaceutical compositions provide for both the correction of inadequate dietary intake of vitamins and minerals as well as antiviral treatment. Mortality from COVID-19 may be increased because of inadequate vitamin levels. Many individuals found to be more susceptible to COVID-19 are deficient in Vitamin D, Vitamin C, and zinc. Including these vitamins in the disclosed anti-coronavirus compositions allows for potential correction of these levels to adequate levels while also providing potential antiviral treatment.

Thirdly, specific ingredients in the disclosed pharmaceutical compositions may provide multiple synergistic effects. There are multiple synergistic effects for these ingredients in combination. For example, the use of zinc with quercetin and EGCG provides a synergistic response in both quercetin and EGCG may act as a zinc ionophore.

Fourthly, the use of multiple ingredients in the disclosed compositions may provide additive effects to overcome inadequate concentrations. Inhibition of SARS-CoV-2 infection is dependent on the plasma concentrations of the inhibitors. Given that the disclosed antiviral compositions have been formulated, first and foremost, to be safe at the intended administered dosage (as mentioned above), single ingredients within the disclosed antiviral compositions alone may not be sufficient to significantly inhibit the coronavirus. However, an additive effect to strongly suppress the virus could be potentially achieved with these ingredients together as many of them target the same enzyme/proteins.

In addition, thus use of multiple ingredients allows for multiple direct and indirect antiviral mechanisms of action against SARS-CoV-2. SARS-CoV-2 has multiple different virulence factors, each of which are potential targets for effective therapy. The use of multiple ingredients in the disclosed compositions allows for the simultaneous use of multiple potential mechanisms of action against SARS-CoV-2 and related viruses.

Furthermore, the use of multiple ingredients provides for potential maintained efficacy despite potential SARS-CoV-2 resistance mutations. In ordinary models of viral evolution, antiviral treatments that are only partially effective may result in a rapid adaptation toward resistance. This can be exacerbated by the large population sizes and high rates of mutation characterizing many viruses. Multiple mutations of the SARS-CoV-2 virus have already been discovered, and mutagenicity within the SARS-CoV-2 genome can potentially lead to reduced efficacy of a single agent over time as well as a general increase in viral resistance. Thus, the use of multiple ingredients in the disclosed anti-coronavirus medications allows for the simultaneous use of differing potential antiviral mechanisms of action against SARS-CoV-2, potentially reducing the risk of the development of resistance mutations in SARS-CoV-2.

FIG. 2 illustrates the lifecycle of the SARS-CoV-2 virus 201 within a human cell 202 and the mechanisms of action of active ingredients of the disclosed pharmacological compositions in accordance with one or more embodiments of the disclosed subject matter. The mechanisms of action of each of the nine active ingredients listed in Table 100 are overlaid onto relevant portions of the image to provide a graphical representation of the multiple mechanisms of action of the disclosed antiviral compositions against SARS-CoV-2. As illustrated in FIG. 2, hesperidin, bovine lactoferrin and quercetin provide collective combative mechanisms for inhibiting the binding of the virus to the cellular wall, thereby inhibiting translocation of the virus through the cell wall. Zinc inhibits SARS-CoV-2 3CL protease (3CLpro), papain-like protease 2 (PLP2), and RNA-dependent RNA polymerase (RdRp) activities, thereby inhibiting replication of the virus after entry into the cell. Zinc also provides immune support and corrects micronutrient deficiencies. The combination of hesperidin, quercetin, EGCG, zinc and copper further inhibit 3CLpro. Caffeic acid inhibits envelop and M-protein production by the virus as well as inhibiting production of the nucleocapsid protein by the virus. Bovine lactoferrin provides immunomodulatory regulation of pro-inflammatory cytokines. Finally, ascorbic acid and cholecalciferol bother provide immune support and/or modulation and correct micronutrient deficiencies.

FIGS. 3A-3B provide another table (Table 300) describing antiviral mechanisms of different ingredients of one or more pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

With reference to FIG. 3A, ascorbic acid (also known as vitamin C) used in combination with one or more other ingredients listed in Table 300 facilitates treatment and prevention of COVID-19 and related diseases generally via general correction of micronutrient deficiencies and indirectly via adaptive and innate immune support, both of which mechanisms have been demonstrated in vivo. The overall prevalence of age-adjusted vitamin C deficiency was 7.1+/−0.9%, with an increasing prevalence in those with a lower socioeconomic status and smokers in the National Health and Nutrition Examination Survey 2003-2004 (NHANES). A history of vitamin C supplement usage or adequate dietary intake significantly decreased the risk of vitamin C deficiency (p<0.05). Vitamin C further indirectly fights against COVID-19 via replenishing Vitamin C reserves during active infection. Treatment of established infections requires significantly higher doses of Vitamin C to compensate for the increased inflammatory response and metabolic demand. Elderly hospitalized patients with acute respiratory infections have been shown to fare significantly better with vitamin C supplementation than those not receiving the vitamin C, and hospitalized patients, in general, have lower vitamin C status than the general population.

Vitamin C further increases EGCG bioavailability, thus providing a synergistic effect when combined with EGCG. In this regard, vitamin C enhances absorption of the EGCG when both are included in the disclosed pharmacological compositions. In vitro studies have demonstrated that vitamin C significantly increases absorption of EGCG. EGCG is a component of the STRI Formula which has direct effects on SARS-CoV-2.

Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. Vitamin C is required for the maturation of T lymphocytes, blood cells that help protect the body from infection. Vitamin C accumulates in neutrophils, or white blood cells, and facilitates their movement as they kill pathogens. In vitro, exogenous vitamin C has been shown to increase the number, proliferation, and function of T lymphocytes. Vitamin C deficiency can result in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels, and the presence of active infection can also potentially further lower vitamin C levels as immune cells increase their use of vitamin C during the inflammatory process. This can become a vicious cycle of sickness and nutrient deficiency. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100-200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher doses of the vitamin to compensate for the increased inflammatory response and metabolic demand. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100-200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.

Lower vitamin C levels are also associated with all-cause mortality and elderly patients with respiratory infections fare better with exogenous vitamin C supplementation. A lower mean vitamin C status has been observed in free-living or institutionalized elderly people, indicated by lowered plasma and leukocyte concentrations, which is of concern because low vitamin C concentrations (<17 μmol/L) in older people (aged 75-82 years) are strongly predictive of all-cause mortality. Acute and chronic diseases that are prevalent in this age group may also play an important part in the reduction of vitamin C reserves. Institutionalization in particular is an aggravating factor in this age group, resulting in even lower plasma vitamin C levels than in non-institutionalized elderly people. It is noteworthy that elderly hospitalized patients with acute respiratory infections have been shown to fare significantly better with vitamin C supplementation than those not receiving the vitamin. Hospitalized patients, in general, have lower vitamin C status than the general population.

Vitamin C has also been shown to help strengthen pulmonary innate immunity in vitro. Vitamin C stimulates repair of the alveolar epithelial lining surface, damaged in acute lung injury caused by sepsis in mice. This protective mechanism in the lung alveolar epithelial surface was shown to be related to ascorbic acid's ability to stimulate the rebuilding of cellular tight junctions.

Similar to vitamin C, cholecalciferol (also known as vitamin D3) used in combination with one or more other ingredients listed in Table 200 facilitates treatment and prevention of COVID-19 and related diseases indirectly via correction of micronutrient deficiencies and immune system modulation. The groups with the highest levels of vitamin D deficiency are the same groups that are at higher risk for COVID-19. In vitro studies have demonstrated that administering vitamin D reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages.

Vitamin D deficiency (VDD) and insufficiency (VDI) are increasing at a global level, and they are associated with increased risk of various diseases. Low vitamin D levels have been found to correlate with higher rates of COVID-19 infection. The mean level of vitamin D3 (average 56 mmol/L, STDEV 10.61) in each country affected by COVID-19 was strongly associated with the number of cases/1M (mean 295.95, STDEV 298.73 p=0.004, respectively with the mortality/1M (mean 5.96, STDEV 15.13, p<0.00001). In addition, the nations with the highest mortality rates (including Italy, Spain and France) also had the lowest average vitamin D3 levels among countries affected by the pandemic. Zinc (as zinc citrate and other forms of zinc) facilitates treatment and prevention of COVID-19 and related diseases by directly inhibiting 3CLpro, PLpro and RdRp. Zinc ions have been found to inhibit SARS-CoV 3CLpro in vitro, which shares significant sequence homology with SARS-CoV-2 3CLpro. Zinc citrate also appears to inhibit PLpro in SARS-CoV which is similar homology to SARS-CoV-2. In addition, zinc citrate inhibits RdRp in SARS-CoV which shares homology to SARS-CoV-2. Positive zinc ions have further been found in vitro to inhibit SARS-CoV replication through direct inhibition of SARS-CoV RdRp.

Vitamin D3 can reduce the cytokine storm induced by the innate immune system as well as regulate adaptive immunity. The innate immune system generates both pro-inflammatory and anti-inflammatory cytokines in response to viral and bacterial infections, as observed in COVID-19 patients. Vitamin D3 can reduce the production of pro-inflammatory Th1 cytokines, such as tumor necrosis factor α and interferon γ. Vitamin D3 also suppresses responses mediated by the T helper cell type 1 (Th1), by primarily repressing production of inflammatory cytokines IL-2 and interferon gamma (INFγ) as has been previously shown.

Zinc used in combination with one or more other ingredients listed in Table 300 further facilitates treatment and prevention of COVID-19 and related diseases generally and indirectly by providing correction of micronutrient deficiencies and immune support. Zinc has significant effects on immune function. Zinc ions are involved in regulating intracellular signaling pathways in innate and adaptive immune cells. Zinc is essential for the immune system and elderly people have an increased probability for zinc deficiency, documented by a decline of serum or plasma zinc levels with age. Although most healthy elderly are not classified as clinically zinc deficient, even marginal zinc deprivation can affect immune function. Several striking similarities in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance towards TH2, decreased response to vaccination, and impaired functions of innate immune cells indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence. Studies with oral zinc supplementation show the potential to improve the immune response of elderly people by restoration of the zinc levels, showing that balancing the zinc status may be a way to healthy aging.

Zinc further facilitates treatment and prevention of COVID-19 and related diseases generally directly by reacting with multiple biological targets of COVID-19. In particular, zinc citrate directly inhibits 3CLpro, PLpro, and RdRp. Zinc ions can inhibit SARS-CoV 3CLpro in vitro, which shares significant sequence homology with SARS-CoV-2 3CLpro. Zinc ions can also inhibit SARS-CoV PLpro in vitro which shares significant sequence homology with SARS-CoV-2 PLpro. Zinc ions further inhibit SARS-CoV in vitro via replication through direct inhibition of SARS-CoV RdRp. SARS-CoV-2 RdRp shares 96.4% genetic homology with SARS-CoV RdRp using standard BLAST reference homology comparisons.

Copper is an essential trace mineral that is not endogenous in humans and must be obtained through diet or supplementation. The disclosed antiviral compositions can include low (e.g., preferably less than 1.0 mg and more preferably less than 0.5 mg) of copper (as copper gluconate) per capsule. The inclusion of copper gluconate, an orally bioavailable copper salt of D-gluconic acid, provides copper supplementation to maintain zinc-copper homeostasis. However, the primary pharmacodynamic effects of copper gluconate as included withing the disclosed antiviral compositions include the inhibition of SARS-CoV-2 3CL protease activity and the exertion of antiviral effects during viral replication.

Quercetin directly facilitates treatment and prevention of COVID-19 and related diseases by directly inhibiting 3CLpro production and also by directly binding to the viral S protein, thereby inhibiting the S protein from binding to the human ACE2 receptor interface. Quercetin inhibits the 3C-like protease (3CLpro) (in vitro) of SARS-CoV using recombinant 3CLpro expressed in Pichia pastoris GS115. As described earlier, SARS-CoV-2 3CLpro has extensive protein structure similarity and genetic homology to the SARS-CoV 3CLpro. Quercetin has significant binding affinity to the SARS-CoV-2 S-protein/ACE2 receptor interface. Quercetin also indirectly fights against COVID-19 and related diseases in combination with zinc. In particular, quercetin is a zinc ionophore and may help potentiate zinc's actions on SARS-CoV-2. Additionally, quercetin may produce antiproliferative effects resulting from the modulation of either EGFR or estrogen-receptor mediated signal transduction pathways.

With reference to FIG. 3B, epigallocatechin gallate or EGCG facilitates treatment and prevention of COVID-19 and related diseases by providing both direct and indirect mechanisms of action. In this regard, EGCG directly inhibits 3CLPro and PLpro. EGCG inhibits the 3C-like protease (3CLpro) of SARS-CoV using recombinant 3CLpro expressed in Pichia pastoris GS115. As described earlier, SARS-CoV-2 3CLpro has extensive protein structure similarity and genetic homology to the SARS-CoV 3CLpro. EGCG has also demonstrated strong binding affinity to SARS-CoV-2 PLpro. PLpro is responsible for the cleavages of N-terminus of the replicase poly-protein to release Nsp1, Nsp2 and Nsp3, which is essential for correcting virus replication. PLpro was also confirmed to be significant to antagonize the host's innate immunity. As an indispensable enzyme in the process of coronavirus replication and infection of the host, PLpro has been a popular target for coronavirus inhibitors. It is very valuable for targeting PLpro to treat coronavirus infections, but no inhibitor has been approved by the FDA for marketing.

EGCG also directly inhibits phospholipase A2 (PLA2) which is important for viral entry. Like other coronaviruses, SARS-CoV-2 replication involves extensive membrane rearrangements in infected cells resulting in the formation of double-membrane vesicles (DMVs) and viral replication/transcription complexes (RTCs). Cytosolic phospholipase A2a (cPLA2a) plays an essential role in the production of DMV-associated coronaviral RTCs. EGCG has been shown in vitro to inhibit PLA2 and therefore may indirectly inhibit SARS-CoV-2 replication. EGCG also indirectly fights against COVID-19 and related diseases in combination with zinc. In particular, EGCG is a zinc ionophore and may help potentiate zinc's actions on SARS-CoV-2.

Caffeic acid is a slightly water-soluble polyphenol with a molar mass of 180.16 g/mol. It is not endogenous in humans and must be obtained through food or supplementation. Based on molecular docking study data, caffeic acid has primary pharmacodynamic effects, including the ability to bind and inhibit SARS-CoV-2 M-protein, E-protein, and N-protein, ultimately affecting SARS-CoV-2 replication and infection. Molecular docking studies have also revealed that caffeic acid may have pharmacological effects allowing it to block SARS-CoV-2 through binding to human host receptor cells. Similarly, and as demonstrated through an in vivo study, caffeic acid has demonstrated ability to inhibit related human coronavirus NL63 (HCoV-NL63) through blocking virus attachment

Hesperidin facilitates treatment and prevention of COVID-19 and related diseases by providing several direct mechanisms of action, including the disruption of the spike protein/ACE2 binding, inhibition of helicase, and inhibition of 3CLpro. Hesperidin is an abundant and inexpensive by-product of citrus cultivation and is the major flavonoid in sweet orange and lemon, originally discovered in 1827. No signs of toxicity have been observed with normal intake of hesperidin. Hesperidin has been found to target both the Spike protein as well as the binding interface between Spike and ACE2. Hesperidin has also shown to have a high binding affinity to helicase. Hesperidin has further been found to have high binding affinity to 3CLpro.

Bovine lactoferrin is a water-soluble protein with a molar mass of 3125.8 g/mol and is obtainable through bovine milk. Bovine lactoferrin has provides pharmacodynamic effects that include its ability to inhibit cell-surface heparan sulfate proteoglycans (HSPGs) and ultimately interfere with viral attachment of host cells. Additionally, the pharmaceutical action of bovine lactoferrin has also been studied in other viruses such as Hepatitis C virus.

FIG. 4 provides a table (Table 400) identifying ingredients of one or more additional pharmacological compositions for treating and preventing disease caused by a coronavirus in accordance with one or more additional embodiments of the disclosed subject matter. Repetitive description of like elements employed in respective embodiments is omitted for sake of brevity.

Table 400 identifies five additional active ingredients that can be included in one or more of the disclosed antiviral compositions to further enhance their therapeutic effect. These additional active agents include luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof. In this regard, in some embodiments, one or more of the disclosed antiviral compositions can include one or more of the active ingredients listed in Table 400. The amounts of these additional active agents as included in one or more of the disclosed antiviral compositions can adhere to the following ranges: about 10.0 mg to about 500 mg of luteolin, more preferably about 50.0 mg to about 300 mg of luteolin, and even more preferably about 100 mg to about 200 mg of luteolin; about 50.0 mg to about 800 mg of myricetin, more preferably about 150 mg to about 600 mg of myricetin, and even more preferably about 250 mg of myricetin; about 50.0 mg to about 300 mg of pomegranate extract; about 50.0 mg to about 300 mg of allicin; about 50.0 mg to about 300 mg of ginger; and about 50.0 mg to about 1000 mg of elderberry extract, more preferably between about 150 mg to about 700 mg of elderberry extract, and even more preferably about 300 mg of elderberry extract.

Luteolin also facilitates treatment and prevention of COVID-19 and related diseases by directly binding to the viral S protein, thereby inhibiting the S protein from binding to the human ACE2 receptor interface. Luteolin has demonstrated high binding affinity to the S-protein:ACE2 receptor interface. In addition, Luteolin has also demonstrated high binding affinity to the S2 subunit of SARS-CoV which shares extensive sequence homology with the S protein S2 subunit of SARS-CoV-2.

Myricetin, (also known as cranberry extract) facilitates treatment and prevention of COVID-19 and related diseases by providing several direct mechanisms of action, including inhibition of helicase via myricetin, and viral entry via PAC-A2. Cranberry extract has demonstrated that myricetin (a common flavonoid found in multiple foods, with the highest concentration in cranberry extract) inhibits the SARS-CoV helicase protein by affecting the ATPase activity. SARS-CoV-2 has 99% genetic sequence homology with SARS-CoV helicase. In addition, cranberry extract inhibits viral attachment of COVID-19 to cells and viral entry into cells by mediating the initial interaction with cell receptor. Cranberry extract with high content of A-type proanthocyanidin dimers (PAC-A2) strongly inhibits and exerts virucidal activity against influenza A and B virus replication by preventing attachment and viral entry into target cells through interference with viral hemagglutinin (HA) glycoprotein.

Pomegranate extract, allicin, and ginger enhance adapted and innated immune support of subjects. When n used in combination with one or more other ingredients listed in Tables 100 and 200, these ingredients further facilitate treatment and prevention of COVID-19 and related diseases by providing mechanisms of immune support and correction of micronutrient deficiencies.

Elderberry facilitates treatment and prevention of COVID-19 and related diseases by directly inhibiting viral replication of HCoV-NL63. Elderberry has been shown to have significant antiviral effects in vitro on viral replication of coronavirus HCoV-NL63 which shares sequence homology with SARS-CoV-2. Especially, the elderberry extract of Sambucus nigra L. exerts the antiviral activity against influenza A and B viruses, human immunodeficiency virus, and the herpes simplex virus type 1. Sambucus nigra phenolic acids like caffeic acid show the highly inhibitory effect on the in vitro replication of influenza A virus.

Also provided are methods of treating and/or preventing disease caused by a coronavirus (and related viruses) in humans and other mammals. The methods typically involve administering one or more of dosages of the disclosed pharmaceutical compositions to the patient daily in an amount sufficient to inhibit growth and/or proliferation of the coronavirus. In various embodiments, the pharmaceutical compounds can be administered orally (e.g., in the form of a capsule, pill, or the like), intravenously or in another suitable form. In certain embodiments the amount is an amount sufficient to exterminate or kill the virus. In some embodiments, the disclosed compositions can be administered to patients who have not contracted COVID-19 (or a related disease) to prevent contracting the disease. In other embodiments, the disclosed compositions can be administered to patients who have tested positive for COVID-19 (or a related disease) to treat the disease to minimize or eliminate the infection (e.g., to kill the virus) and/or to otherwise facilitate recovery from the disease.

FIG. 5 provides a high-level flow diagram of a method 500 for treating and preventing disease caused by a coronavirus in accordance with one or more embodiments of the disclosed subject matter.

In accordance with method 500, at 502, the method comprises administering an effective amount of an antiviral composition to a patient, the antiviral composition having active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin, and derivatives of the active ingredients. In some embodiments, the antiviral composition comprises all nine of the above listed active ingredients. In other embodiments, the antiviral composition comprises a subset of the nine listed active ingredients. At 502, the method further comprises inhibiting infection of the patient of by a coronavirus based on the administering, the coronavirus comprising SARS-CoV-2. The effective dose can be tailored based on the patient and the severity of the illness. In some implementations, the antiviral composition can be administered orally in the form of a pill or capsule. For example, each pill or capsule can comprise the relative amounts of the respective active ingredients described above. In some implementations of these embodiments, an effective dose can comprise three capsules taken twice daily for about 10 days.

FIG. 6 provides a high-level flow diagram of another method 600 for treating coronavirus disease (COVID-19) in a patient in accordance with one or more embodiments of the disclosed subject matter. Repetitive description of like elements employed in respective embodiments is omitted for sake of brevity.

In accordance with method 600, at 602, the method comprises administering an effective amount of an antiviral composition to a patient with coronavirus disease (COVID-19), the antiviral composition having active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin, and derivatives of the active ingredients. In some embodiments, the antiviral composition comprises all nine of the above listed active ingredients. In other embodiments, the antiviral composition comprises a subset of the nine listed active ingredients. At 604, method 600 further comprises facilitating eradicating the coronavirus disease from the patient based on the administering. The effective dose can be tailored based on the patient and the severity of the illness. In some implementations, the antiviral composition can be administered orally in the form of a pill or capsule. For example, each pill or capsule can comprise the relative amounts of the respective active ingredients described above. In some implementations of these embodiments, an effective dose can comprise three capsules taken twice daily for about 10 days.

FIG. 7 provides a high-level flow diagram of a method 700 for treating and preventing a viral disease (not limited to COVID-19) in accordance with one or more embodiments of the disclosed subject matter.

In accordance with method 700, at 702, the method comprises administering an effective amount of an antiviral composition to a patient, the antiviral composition having active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients. In some embodiments, the antiviral composition comprises all nine of the above listed active ingredients. In other embodiments, the antiviral composition comprises a subset of the nine listed active ingredients. At 702, the method further comprises inhibiting infection of the patient of by a virus based on the administering. The effective dose can be tailored based on the patient and the severity of the illness. In some implementations, the antiviral composition can be administered orally in the form of a pill or capsule. For example, each pill or capsule can comprise the relative amounts of the respective active ingredients described above. In some implementations of these embodiments, an effective dose can comprise three capsules taken twice daily for about 10 days.

FIG. 8 provides a high-level flow diagram of another method 800 for treating a viral disease (not limited to COVID-19) in a patient in accordance with one or more embodiments of the disclosed subject matter. Repetitive description of like elements employed in respective embodiments is omitted for sake of brevity.

In accordance with method 700, at 702, the method comprises administering an effective amount of an antiviral composition to a patient with a viral disease, the antiviral composition having active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc (as zinc citrate dihydrate or other forms of elemental zinc), copper (as copper gluconate or other forms of elemental copper), epigallocatechin gallate (or other flavonoids found within green tea), quercetin (as quercetin dihydrate or other forms of quercetin), hesperidin, caffeic acid, bovine lactoferrin and derivatives of the active ingredients. In some embodiments, the antiviral composition comprises all nine of the above listed active ingredients. In other embodiments, the antiviral composition comprises a subset of the nine listed active ingredients. At 804, method 800 further comprises facilitating eradicating the viral disease from the patient based on the administering. The effective dose can be tailored based on the patient and the severity of the viral disease. In some implementations, the antiviral composition can be administered orally in the form of a pill or capsule. For example, each pill or capsule can comprise the relative amounts of the respective active ingredients described above. In some implementations of these embodiments, an effective dose can comprise three capsules taken twice daily for about 10 days.

It should be noted that, for simplicity of explanation, in some circumstances the computer-implemented methodologies are depicted and described herein as a series of acts. It is to be understood and appreciated that the subject innovation is not limited by the acts illustrated and/or by the order of acts, for example acts can occur in various orders and/or concurrently, and with other acts not presented and described herein.

The term “facilitate” as used herein is in the context of a system, device or component “facilitating” one or more actions or operations, in respect of the nature of complex computing environments in which multiple components and/or multiple devices can be involved in some computing operations. Non-limiting examples of actions that may or may not involve multiple components and/or multiple devices comprise transmitting or receiving data, establishing a connection between devices, determining intermediate results toward obtaining a result (e.g., including employing ML and/or AI techniques to determine the intermediate results), etc. In this regard, a computing device or component can facilitate an operation by playing any part in accomplishing the operation. When operations of a component are described herein, it is thus to be understood that where the operations are described as facilitated by the component, the operations can be optionally completed with the cooperation of one or more other computing devices or components, such as, but not limited to: sensors, antennae, audio and/or visual output devices, other devices, etc.

In addition, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.” That is, unless specified otherwise, or clear from context, “X employs A or B” is intended to mean any of the natural inclusive permutations. That is, if X employs A; X employs B; or X employs both A and B, then “X employs A or B” is satisfied under any of the foregoing instances. Moreover, articles “a” and “an” as used in the subject specification and annexed drawings should generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form. As used herein, the terms “example” and/or “exemplary” are utilized to mean serving as an example, instance, or illustration. For the avoidance of doubt, the subject matter disclosed herein is not limited by such examples. In addition, any aspect or design described herein as an “example” and/or “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs, nor is it meant to preclude equivalent exemplary structures and techniques known to those of ordinary skill in the art.

What has been described above include mere examples of systems and computer-implemented methods. It is, of course, not possible to describe every conceivable combination of components or computer-implemented methods for purposes of describing this disclosure, but one of ordinary skill in the art can recognize that many further combinations and permutations of this disclosure are possible. Furthermore, to the extent that the terms “includes,” “has,” “possesses,” and the like are used in the detailed description, claims, appendices and drawings such terms are intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim.

The descriptions of the various embodiments have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein. 

What is claimed is:
 1. A composition for the treatment and prevention of disease caused by a coronavirus, the composition having active ingredients comprising: ascorbic acid, cholecalciferol, zinc, copper, epigallocatechin gallate, quercetin, hesperidin, caffeic acid, and bovine lactoferrin.
 2. The composition of claim 1, wherein the active ingredients further comprise derivatives of the active ingredients.
 3. The composition of claim 1, wherein the active ingredients further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof.
 4. The composition of claim 1, wherein the zinc comprises zinc citrate dihydrate, the copper comprises copper gluconate, and the quercetin comprises quercetin dihydrate.
 5. The composition of claims 1, wherein the coronavirus comprises is selected from the group consisting of: coronavirus comprises severe acute respiratory syndrome (SARS) coronavirus and derivatives thereof, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and derivatives thereof.
 6. The composition of claim 1, wherein the disease comprises coronavirus disease (COVID-19) in humans and other mammals.
 7. The composition of claim 1, wherein the composition is discretized into units, and wherein each unit comprises about 30.0 milligrams (mg) to about 120 mg of ascorbic acid, about 5.0 micrograms (μg) to about 50.0 μm of cholecalciferol, about 0.5 mg to about 20 mg of zinc, about 0.05 mg to about 5.0 mg of copper, about 10.0 mg to about 100 mg of epigallocatechin gallate, about 50.0 mg to about 150 mg of quercetin, about 30.0 mg to about 120 mg of hesperidin, about 10.0 mg to about 100 mg of caffeic acid, and about 10.0 mg to about 100 mg of bovine lactoferrin.
 8. The composition of claim 1, wherein the composition further comprises at least one of a pharmaceutically acceptable additive, excipient, or filler.
 9. The composition of claim 7, wherein the composition is in a unit form selected from the group consisting of: an oral capsule, a tablet, a cachet, a liquid and a powder.
 10. The composition of claim 1, wherein the composition treats and inhibits infection of the virus in human cells using different mechanisms of action attributed to one or more synergistic combinations of the active ingredients.
 11. The composition of claim 1, wherein the composition treats and inhibits infection of the virus in human cells based on direct or indirect disruption of one or more biological targets of the coronavirus caused by one or more of the active ingredients.
 12. The composition of claim 1, wherein the one or more biological targets are selected from a group consisting of: spike protein, helicase (nsp13), RNA-dependent RNA polymerase (RdRp), propapain-like protease (PLpro), and chymotrypsin-like protease (3CLpro).
 13. A method for treating or inhibiting a disease in a patient caused by a virus comprising administering an effective amount of an antiviral composition to the patient, the antiviral composition having active ingredients comprising: ascorbic acid, cholecalciferol, zinc, copper, epigallocatechin gallate, quercetin, hesperidin, caffeic acid, and bovine lactoferrin.
 14. The method of claim 13, wherein the active ingredients further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof.
 15. The method of claims 13, wherein the virus comprises severe acute respiratory syndrome (SARS) coronavirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and derivatives thereof.
 16. The method of claim 13, wherein the disease comprises coronavirus disease (COVID-19) in humans and other mammals.
 17. The method of claims 13, further comprising: inhibiting infection of the virus in cells of the patient based on the administering; or eradicating the virus from cells of the patient based on the administering.
 18. The method of claim 17, wherein at least one of the inhibiting or the eradicating is based on direct or indirect disruption of one or more biological targets of the virus caused by different mechanisms of action of the active ingredients.
 19. The method of claims 18, wherein the one or more biological targets are selected from a group consisting of: spike protein, helicase (nsp13), RNA-dependent RNA polymerase (RdRp), propapain-like protease (PLpro), and chymotrypsin-like protease (3CLpro).
 20. The method of claim 13, wherein the administering comprises orally administering one or more dosages of the antiviral composition to the patient daily.
 21. An antiviral composition comprising two or more active ingredients selected from the group consisting of: ascorbic acid, cholecalciferol, zinc, copper, epigallocatechin gallate, quercetin, hesperidin, caffeic acid, and bovine lactoferrin.
 22. The antiviral composition of claim 21, wherein the antiviral composition comprises five or more active ingredients selected from the group.
 23. The antiviral composition of claim 21, wherein the antiviral composition comprises seven or more active ingredients selected from the group.
 24. The antiviral composition of claim 21, wherein the antiviral composition comprises all of the active ingredients included in the group.
 25. The antiviral composition of claim 21, wherein the active ingredients further comprise one or more ingredients selected from the group consisting of: luteolin, myricetin, pomegranate extract allicin, ginger, elderberry, and derivatives thereof.
 26. The antiviral composition of claim 21, wherein the antiviral composition treats and inhibits infection and disease caused by a coronavirus. 